A wide variety of diseases have a significant genetic component, including major causes of morbidity and mortality in the western world. Many of these diseases are also angiogenesis dependent. In humans, common polymorphisms, although more subtle in effect than rare mutations that cause Mendelian disease, are expected to have greater overall effects on human disease. Thus, common polymorphisms in angiogenesis-regulating genes may affect the response to an angiogenic stimulus and thereby affect susceptibility to or progression of such diseases. Candidate gene studies have identified several associations between angiogenesis gene polymorphisms and disease. Similarly, emerging pharmacogenomic evidence indicates that several angiogenesis-regulating polymorphisms may predict response to therapy. In contrast, genome-wide association studies have identified only a few risk alleles in obvious angiogenesis genes. As in other traits, regulatory polymorphisms appear to dominate the landscape of angiogenic responsiveness. Rodent assays, including the mouse corneal micropocket assay, tumor models, and a macular degeneration model have allowed the identification and comparison of loci that directly affect the trait. Complementarity between human and animal approaches will allow increased understanding of the genetic basis for angiogenesis-dependent disease.